Effective drug therapy generally requires maintained drug levels in the blood stream for extended periods of time. Standard tablets, however, generally disintegrate quickly and release all the active components over a relatively short period of time. With these dosage forms drug levels are maintained by administering the tablets several times a day. This is inconvenient and frequently leads to poorer patient compliance. Thus it is desirable to identify drug delivery systems which will produce constant drug levels in the blood for extended time periods. It is thought that to obtain a constant drug level in the blood a drug delivery system must release the drug at a constant rate. To achieve this constant rate, several mechanisms including osmosis, diffusion and dissolution, and dosage form modifications have been investigated, for example as described in Ho-Wah Hui et al., Chapter 9 in “Controlled Drug Delivery”: Fundamentals and Applications (2nd Ed.), Marcel Dekker, New York, 1987. There remains, however, a clear and continuing need for simple inexpensive dosage forms which efficiently and reliably deliver active compounds over extended time periods.
Drug delivery systems frequently include passive impermeable coatings which surround a core composition containing the active drug substance and excipients. This coating frequently plays an important role in maintaining the structural integrity of the device during the drug release period. If the impermeable coating does not dissolve or disintegrate prior to passage through the gastrointestinal system, a “ghost” residue will remain which can be uncomfortable or undesirable to void. Furthermore, passage of these residual coatings through the GI tract potentially can damage the intestinal mucosa.
Attempts have been made to achieve constant rates of drug release by controlling the surface area of tablets. Examples of such attempts are described in Stephenson et al. (UK Patent No. 1,022,171), Reid (U.S. Pat. No. 3,279,995) and DePrince (U.S. Pat. No. 4,663,147). However, such systems have not been completely successful usually either due to improper design of the system or due to a lack of appropriate and available manufacturing technology.
Another approach has been to coat the active component with impermeable coatings which limit access of the fluid media to the active component and slow dissolution of the core. Staniforth (U.S. Pat. No. 5,004,614) employs a coated tablet containing holes in the coating to limit contact with the surrounding medium. Both dissolution and diffusion process can be exploited to attempt to regulate drug release from delivery devices. Ranade (U.S. Pat. No. 4,803,076) has disclosed a dissolution and diffusion device for the controlled release of a substance into a fluid media at a substantially constant rate wherein the substance is contained in a shape substantially that of a truncated cone in which the sides and base (but not the top) of the cone are coated with an impermeable wall or coating. A related design was disclosed by Cremer (U.S. Pat. No. 6,264,985). McMullen (U.S. Pat. No. 4,816,262) describes a controlled release tablet which includes a solid core having a hydrophilic releasable agent. The core has a central hole and is coated on all faces except that formed by the central hole. The thickness gradually increases from the central hole to the outer border and forms a concave disk containing a hydrophilic releasable agent. Chopra (U.S. Pat. No. 5,342,627) describes a tablet shaped core in which the thickness decreases from the center of the tablet to the periphery and the exposed surface from which release occurs is a cylindrical band around the outer perimeter of the tablet. Kim (U.S. Pat. No. 6,110,500) has disclosed a tablet for controlled release of an active ingredient from a core having a donut-like configuration with a cylindrical hole extending through the center of the core. The core comprises a releasable substance and at least one hydrophilic, water-soluble polymeric carrier. These hydrophilic polymeric carriers are swellable and/or erodable. Swelling of the polymer, however, can deform the controlled release device and alter the release rates. The core is coated with a hydrophobic water insoluble material except the area defined by the cylindrical hole through the core. Cremer (U.S. Pat. No. 5,853,760) teaches a device for the controlled release of active substances into fluid media from an active substance-containing matrix, the active substance releasing surfaces of which are, at least partially, covered by an erodible solid. The delivery characteristics depend on the surfaces coated and the thickness and geometry of the coating which erodes over the delivery period to expose additional surfaces of the matrix to the fluid medium. Shah and Britten (U.S. Pat. No. 5,922,342) disclose a controlled release composition with a compressed core having two parallel planar surfaces containing at least 90% of a non-disintegrating therapeutic agent(s) and optionally containing 0-10% of non-disintegrating ingredients that are conventional in tablet making such as binders, lubricants, compression aids, flow aids and the like. The device allows zero-order release of a drug throughout the delivery period. The core is free of materials that can cause swelling or disintegrate. A seal coating consisting of a film of impermeable material surrounds the core except the two parallel planar surfaces (i.e. on all the later surfaces. The seal coating serves to protect the lateral surfaces of the core.
The osmotically driven systems (e.g. U.S. Pat. No. 4,111,202) release the drug at a constant rate for as long as the concentration of the osmotic agent in the system is at the saturation point. When the concentration of the osmotic agent falls below the saturation point, the release rate declines parabolically towards zero as described in F. Theeuwes et al. Elementary Osmotic Pump for indomethacin, J. Pharm. Sci., 72, 253, (1983).
Dissolution-controlled and diffusion controlled devices consist of a pharmaceutical agent mixed with inert ingredients compressed into tablets. A dissolution-controlled device contains a shaped core, optionally partially coated with an insoluble polymeric coating, in which the exposed portion of the core dissolves into or is eroded by the surrounding media whereby the active compound is released into the media. The shaped core contains the active ingredient optionally combined with release-modifying agents, buffers and binders. A dissolution device is suitable for formulating hydrophobic and hydrophilic compounds whereas a diffusion device is especially suited to deliver hydrophilic compounds. A diffusion-controlled device contains a pharmaceutical agent uniformly distributed in an insoluble porous polymeric matrix. The insoluble matrix is present throughout the delivery period and the dimensions of the device remain constant. As the drug becomes depleted in proximity of the exposed surface, the release rate also becomes a function of the diffusion path length through the insoluble matrix through which the remaining drug must diffuse to reach the exposed surface in contact with the dissolution media.
Some therapeutic regimens require administering a varying quantity of the active substance. Attempts have been made to design dosage forms which produce variable release rates or pulsatile release but these have not been reliable or cost effective since they frequently possess complex architectures which are difficult to fabricate and are structurally weak. For example, Chopra (U.S. Pat. No. 5,342,627) teaches that “the geometrical profile of the cavity and core of the diffusion device may be such that ‘pulses’ of the active substance are release at predetermined points in the total dissolution time. Thus, the profile of the cavity ‘walls’ may be varied to provide pre-determined changes in the surface are so as to provide pulses of activity.” There is, however, no explanation of geometries which will produce nonlinear release nor does the geometry of the device allow for ready modification.
The release rate of a chemical from a compressed soluble disc in a dissolution-controlled device, dm/dt, can be expressed as:                                           ⅆ            m                                ⅆ            t                          =                  AC          ⁢                                    ⅆ              x                                      ⅆ              t                                                          (                  Equation          ⁢                                           ⁢          1                )                            where: A is the surface area;                    C is the concentration of the chemical; and            dx/dt is the mass erosion rate.                        
Equation (1) predicts that the release rate will be proportional to the exposed surface area if the mass erosion rate is constant and the chemical substance is uniformly distributed throughout the core of the tablet. In reality, however, the rate of dissolution is not a simple function of surface area alone, rather it is a complex function of changing size and the shape of the disc itself, as well as fluid dynamics of the adjacent solvent layer as described in F. J. Rippie and J. R. Johnson, Regulation of Dissolution Rate by Pellet Geometry, J. Pharm. Sci., 58, 428 (1969). Nevertheless, if the device is designed to provide a constant surface area over a substantial portion of the delivery period, a constant dissolution rate can be expected. (D. Brooke and R. J. Washkuhn, Zero-order Drug Delivery Systems: Theory and Preliminary Testing, J. Pharm. Sci., 1979 66:159).
In the diffusion mechanism, the release of chemical from a solid matrix by diffusion can be represented by Equation 2:                                           ⅆ            q                                ⅆ            t                          =                              -            DA                    ⁢                                    ⅆ              c                                      ⅆ              r                                                          (                  Equation          ⁢                                           ⁢          2                )                            where q is the mass of chemical being transferred;                    t is the time;            c is the chemical concentration;            r is the diffusion path length;            A is the area for the mass transport; and,            D the diffusion coefficient of the chemical.                        
According to the above equation, the chemical release rate decreases as the diffusion path length r increases. Since r cannot be kept constant, a constant release rate can be maintained by increasing the concentration of active compound by exposing greater surface area to compensate for the increase in diffusion distance through the matrix.
Existing devices have features that limit their applicability and practical production of effective controlled release agents has proven difficult. Devices which do not provide for adequate quantities of a dissolution regulator have limited flexibility to optimize the delivery rate. Water-soluble compounds will be released too rapidly when present in very high concentration in dissolution devices. Devices which do not provide for insoluble modifiers are incapable of functioning as diffusion devices which are desirable when delivering hydrophobic compounds. If improperly designed, the release rate from controlled release devices may vary over the release period. Osmotic devices have a lag time until the desired release rate is achieved whereas the present devices begin to deliver the active chemical upon contact with the fluid medium. The release from osmotic systems also decreases suddenly once the osmotic regulant is depleted from the device leaving residual active compound in the device. Diffusion-controlled devices in which the active compound must diffuse through an insoluble matrix may have a lag time or slow release rate and be voided intact before the complete release of the active ingredient.
Premature separation of the impermeable coating from the core can cause “dose dumping” as the uncoated core disintegrates Impermeable coatings in existing devices have no reliable disintegration mechanism which can lead to evacuation of the intact coating or release device. Furthermore the amount of active substance which can be accommodated by these known devices is often limited by practical difficulties scaling the size and geometry of these architecturally complex devices. The rate of release from devices with a swellable and/or erodible polymer decrease in the later stages of drug release whereas dissolution devices afford constant release throughout the delivery period. The release rate from swellable cores also can be erratic due to the hydrodynamic conditions in the gastrointestinal tract as the swellable polymers are easily abraded. Release from an erodible matrix decreases as the surface area of the erodible surface decreases. Diffusion devices often exhibit non-zero order release as the diffusion path between the residual active substance and the fluid medium increases. A variety of geometrical designs have been suggested to overcome these problems; however, implementing these designs has often been problematical.
The release rate from these devices is dependent on a variety of factors. The geometrical shape of the matrix is an important parameter. Other factors include, but not limited to, the specific properties of the substances used, e.g., molecular mass, solubility, swelling temperature and glass transition temperature of the components of the device. When the release requires diffusion through a matrix, the main parameters include the size of the surface, the matrix volume, the diffusion coefficient, the concentration and solubility of the active substance in the matrix, the porosity and tortuosity of the matrix, and the diffusion resistance between the matrix and the fluid medium.
Many controlled release delivery devices incorporate polymeric coatings that are essentially water insoluble and consequently have low permeability to both water and the active component in the device. Depending upon the physical principles utilized to control delivery of the active ingredient, these coatings may be modified to alter their permeability. Several approaches to controlled drug delivery devices utilize a core containing the active ingredient with an impermeable polymeric coat containing particulate pore-forming materials which are soluble in water or in gastrointestinal fluids. Lindahl and Erlandsson (U.S. Pat. Nos. 4,557,925; 4,629,619 and 4,629,620) utilize pore-forming materials that dissolve or leach out of the coating which creates paths or channels allowing ingress of the surrounding fluids which dissolve the active compound and produce saturated solutions of the active compound in the core which subsequently egress through the same channels. The release rates in these relatively simple devices are predominantly a function of the time required for dissolution of the particles and the size and density of the channels. These variables depend on the solubility and particle size of the pore-forming material and the concentration in the impermeable coat. Berliner and Nacht (U.S. Pat. No. 5,849,327) disclosed delivery devices in which the pore-forming materials are degraded by colon specific bacteria resulting in release of the active ingredient in the colon. Lindahl and Ekland (U.S. Pat. No. 4,824,678) describe delivery devices utilizing this principle by incorporating the active ingredient in the core and in the pore-creating particles which produces a burst of active ingredient as the pores are formed.
Osmotic delivery devices also have incorporated pore-forming materials within impermeable or semipermeable polymeric coatings to provide channels for osmotic pumping of the contents into the external medium. For example, Haslam and Rork (U.S. Pat. No. 4,886,668) describe an osmotic device wherein pore-forming materials are incorporated with a semipermeable coating. Ingress of water occurs through the semipermeable coating and dissolution or leaching of the pore-forming materials provides egress channels for the concentrated solution of active component formed in the core.
Regardless of the physical principles underlying the design and operation of the delivery device, the pore-forming compounds are incorporated to provide a pathway to move fluids through the impermeable polymeric coating.
There remains a need for effective and adaptable systems for controlled release of active chemicals with improved performance. The devices in the present invention can be readily scaled to different proportions that will accommodate differing quantities of the active chemical and which, therefore, have the capacity for longer release periods. With the present system the core is slow dissolving, which means that “dose dumping” is not as prevalent as in other chemical delivery systems, and there is minimal effect of hydrodynamic conditions prevailing in the stomach as only the peripheral face of the core is exposed. The present system also provides a reliable and predictable means to insure disintegration of the insoluble impermeable coating to avoid elimination of the intact device. Furthermore the rate of disintegration of the coating can be manipulated by adjusting the size, density and composition of the pore-forming materials.